RT Journal
A1 Menzies L, Ooi C, Kamath S, et al
T1 EFfects of γ-aminobutyric acid–modulating drugs on working memory and brain function in patients with schizophrenia
JF Archives of General Psychiatry
JO Archives of General Psychiatry
YR 2007
FD February 1
VO 64
IS 2
SP 156
OP 167
DO 10.1001/archpsyc.64.2.156
UL http://dx.doi.org/10.1001/archpsyc.64.2.156
AB Context
Cognitive impairment causes morbidity in schizophrenia and could be due to abnormalities of cortical interneurons using the inhibitory neurotransmitter γ-aminobutyric acid (GABA).Objectives
To test the predictions that cognitive and brain functional responses to GABA-modulating drugs are correlated and abnormal in schizophrenia.Design
Pharmacological functional magnetic resonance imaging study of 2 groups, each undergoing scanning 3 times, using an N-back working memory task, after placebo, lorazepam, or flumazenil administration.Setting and Participants
Eleven patients with chronic schizophrenia were recruited from a rehabilitation service, and 11 healthy volunteers matched for age, sex, and premorbid IQ were recruited from the local community.Intervention
Participants received 2 mg of oral lorazepam, a 0.9-mg intravenous flumazenil bolus followed by a flumazenil infusion of 0.0102 mg/min, or oral and intravenous placebo.Main Outcome Measures
Working memory performance was summarized by the target discrimination index at several levels of difficulty. Increasing (or decreasing) brain functional activation in response to increasing task difficulty was summarized by the positive (or negative) load response.Results
Lorazepam impaired performance and flumazenil enhanced it; these cognitive effects were more salient in schizophrenic patients. Functional magnetic resonance imaging demonstrated positive load response in a frontoparietal system and negative load response in the temporal and posterior cingulate regions; activation of the frontoparietal cortex was positively correlated with deactivation of the temporocingulate cortex. After placebo administration, schizophrenic patients had abnormally attenuated activation of the frontoparietal cortex and deactivation of the temporocingulate cortex; this pattern was mimicked in healthy volunteers and exacerbated in schizophrenic patients by lorazepam. However, in schizophrenic patients, flumazenil enhanced deactivation of the temporocingulate and activation of the anterior cingulate cortices.Conclusions
The GABA-modulating drugs differentially affect working memory performance and brain function in schizophrenia. Cognitive impairment in schizophrenia may reflect abnormal inhibitory function and could be treated by drugs targeting GABA neurotransmission.